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Biomedical subjects

G Köhler

Publications and source records attributed to G Köhler.

At least 91 records · Page 5Linked to original sources
PubMed1997

[Severe cardiac failure in Kearns-Sayre syndrome].

Mitochondrial disorders are a group of diseases that can affect virtually all organ systems. A 19 year old man was seen in 1993 with neurologic abnormalities consisting of impaired function of muscles, diplopia, progressive loss of vision, impaired phonation and swallowing, during the last 10 years. Physical examination disclosed moderate wasting of the four limb muscles, mild motor weakness of neck muscles, symmetrical hyporeflexia, cerebellar dysfunction, severe external ophtalmoplegia and ptosis. Fundii oculi examination showed retinitis pigmentosa. The electromyogram demonstrated myopathic changes with normal nerve conduction velocities. The cerebrospinal fluid was normal, except for a mild increase in lactic acid. Histochemical study of a muscle biopsy specimen demonstrated ragged red fibers and increase of the subsarcolemal oxidative activity of mitochondriae. The diagnosis of Kearns-Sayre disease was confirmed and he was discharged advising physical therapy. On February 1995, he was again admitted, this time with right cardiac failure and worsening of all his previous symptoms and signs. He complained of myalgias and his muscle weakness was more striking on clinical examination. Echocardiography showed biventricular dilatation and left ventricular hypertrophy with preserved systolic function. A new muscle biopsy revealed an heteroplasmic deletion of 5 Kb with 80% of mutant mitochondrial DNA. In brief, we report a patient with the clinical phenotype of Kearns-Sayre syndrome who presented an acute congestive cardiac failure due to cardiomyopathy, an association which has seldom been, reported in the literature.

Adult↗
PubMed1996

Systemic hematological effects of granulocyte colony-stimulating factor produced by irradiated gene-transfected fibroblasts.

Although long-term expression of therapeutic molecules is necessary for the treatment of permanent deficiencies, short-term expression of therapeutic molecules inducing local or systemic effects is preferable in clinical situations where temporary substitution is the goal. One such clinical setting is the administration of hematopoietic growth factors in cancer chemotherapy-induced myelosuppression. Several plasmid vectors containing the human granulocyte colony-stimulating factor (G-CSF) gene under transcriptional control of different regulatory elements were constructed. In vitro production of G-CSF by nonvirally transfected murine fibroblast clones initially increased after lethal irradiation and was detectable for at least 12 days. We also demonstrate that a single injection of irradiated G-CSF-secreting fibroblasts leads to accelerated hematopoietic recovery and mobilization of committed peripheral blood progenitor cells equivalent to that achieved by twice daily s.c. administration of high doses of recombinant human G-CSF. Using dicistronic vectors, high levels of G-CSF secretion were also obtained in human fibroblasts.

Animals↗
PubMed1996

[Primary pigmented nodular adrenocortical dysplasia. A rare cause of Cushing's syndrome].

HISTORY AND CLINICAL FINDINGS: A 29-year-old woman was found to have arterial hypertension (175/115 mm Hg). The 24-hour profile showed no diurnal cortisol variations with normal concentrations and 24-hour urinary cortisol was normal. 14 months later there was definite hypercortisolism with discrete Cushing signs and no amenorrhoea. She also had signs of depression. INVESTIGATIONS: Routine laboratory tests were unremarkable. ACTH and dehydroepiandrosterone levels were reduced and there was marked hypercortisolism (600 micrograms/24h). Bone densitometry showed osteoporosis. The low- and high-dose dexamethasone inhibition tests showed no suppression of 24-hour urinary cortisol, raising the suspicion of adrenal cortical adenoma or carcinoma. Magnetic resonance imaging (MRI) of both adrenals was normal, and scintigraphy showed physiological storage. MRI of the skull was normal. TREATMENT AND COURSE: As ACTH-independent hypercortisolism had been proven, unilateral adrenalectomy was performed. The specimen showed primary pigmented nodular adrenocortical dysplasia (PPNAD). While cortisol levels and blood pressure were at first normal, hypercortisolism had recurred 5 months postoperatively. The other adrenal was removed and showed a similar histology. A malignant melanoma of the shoulder was also found, perhaps part of a Carney syndrome. CONCLUSION: PPNAD should be included in the differential diagnosis of an ACTH-independent Cushing's syndrome with normal adrenal on imaging, perhaps as part of a Carney syndrome.

Adrenal Cortex↗
PubMed1996

In vitro differentiation of CD34+ hematopoietic progenitor cells toward distinct dendritic cell subsets of the birbeck granule and MIIC-positive Langerhans cell and the interdigitating dendritic cell type.

We have demonstrated recently that Birbeck granule-positive Langerhans cells (LC) can be derived from CD34+ peripheral blood progenitor cells in the presence of a seven-cytokine cocktail (CC7-7). Here, we show that the sequential use of early-acting hematopoietic growth factors, stem cell factor, interleukin (IL)-3, and IL-6, followed on day 8 by differentiation in the two-factor combination IL-4 plus granulocytemacrophage colony-stimulating factor (GM-CSF) (CC4GM) is more efficient and allows the cells to be arrested in the LC stage for more than 1 week while continuous maturation occurs in CC7-7. Maturation of LC to interdigitating dendritic cells (DC) could specifically be induced within 60 hours by addition of tumor necrosis factor-alpha (20 ng/mL) or lipopolysaccharide (100 ng/mL). Using LC that had been enriched to greater than 90% CD1a+ cells by an immunoaffinity column, we were able to define clear-cut differences between LC and DC that corroborate data of the respective cells derived from epithelial borders (LC) or from lymph nodes (LN) and spleen (DC). Thus, molecules and functions involved in antigen (AG) uptake and processing were highly expressed in LC, while those involved in AG presentation were at maximum in DC. LC were CD1a+2 DR+2, CD23+, CD36+, CD80-, CD86-, and CD25-, while DC were CD1a+/- DR+3, CD23-, CD36-, CD80+, CD86+2, and CD25+, CD40 and CD32 were moderately expressed and nearly unchanged on maturation, in contrast to monocyte-derived DC. Macropinocytosis of fluorescein isothiocyanate-dextran was dominant in LC, as were multilamellar major histocompatibility complex (MHC) class II compartments (MIICs), which were detected by electron microscopy. The functional dichotomy of these cell types was finally supported by testing the AG-presenting cell function for tetanus toxoid to primed autologous T-cell lines, which was optimal when cells were loaded with AG as LC and subsequently induced to become DC.

Antigen Presentation↗
PubMed1996

IL-4-deficient Balb/c mice resist infection with Leishmania major.

Mice with a genetically engineered deficiency for either IL-4 or IFN-gamma R1 (single mutants), and IL-4/IFN-gamma R1 (double mutants) on the Balb/c and 129Sv background were used to study the course of infection with Leishmania major. In contrast to genetically resistant 129Sv wildtype mice, IL-4/IFN-gamma R1 double mutant mice developed fetal disease with parasite dissemination to visceral organs similar to mice lacking IFN-gamma R1 only. Balb/c mice, which are exquisitely susceptible to L. major, were rendered resistant to infection by disruption of the IL-4 gene. As compared to homozygous IL-4+/- mice, heterozygous IL-4+/- mice, heterozygous IL-4+/- animals consistently developed smaller lesions with less ulceration and necrosis, indicating the likelihood of gene-dosage effects. This implicates that the magnitude of the IL-4 response determines the severity of disease. CD4+ T cells of IL-4-deficient mice showed impaired Th2 cell development, as assessed by quantitative RT-PCR of characteristic cytokines. Development of resistance is not explained by default Th1 development, because this was observed only at very late stages of infection. Moreover, the induction of inflammatory cytokines (e.g., IL-1 alpha, IL-1 beta, TNF-alpha, IL-12) together with iNOS in the lesion and draining lymph nodes was not altered in the absence of IL-4.

Animals↗
PubMed1996

Non-tolerant B cells cause autoimmunity in anti-CD8 IgG2a-transgenic mice.

Using a pair of gamma 2a/chi immunoglobulin genes, transgenic mice were generated to study tolerance induction in B cells that express IgG2a autoantibodies. The transgenic IgG2a specifically binds CD8 alpha chains of the CD8.2 allotype expressed on the surface of CD8+ T cells, but not CD8 molecules expressed by the CD8.1 allele. Thus, IgG2a transgenic mice expressing the CD8.1 allele were used as controls to monitor B cell development and mice expressing CD8.2 were used to study B cell tolerance. Both types of mice showed transgenic gamma 2a expression on the surface of B cells. Expression of endogenous heavy chain alleles was strongly inhibited in immature B cell subsets, whereas mature B cells co-expressed transgenic gamma 2a and endogenous IgM/D. The transgenic chi chain expression leads only to partial allelic exclusion of endogenous light chains. B cells that express high levels of transgenic CD8.2-specific IgG2a were identified using soluble CD8-Ig. In CD8.1+ and in CD8.2+ mice, we found no differences in expression and maturation of transgenic anti-CD8.2 IgG2a+ B cells. High levels of serum anti-CD8.2 IgG2a antibodies led to the elimination of CD8+ T cells, causing a severe defect in cytotoxic immune responses. These results show that tolerance induction is incomplete in the CD8.2+ mice, either because IgG2a+ B cells are resistant to censoring mechanisms or because the secreted CD8-specific IgG2a antibodies render the CD8 autoantigen inaccessible to the B cells. This contrasts strongly with the efficient induction of B cell tolerance in mice expressing anti-CD8.2 IgM autoantibodies.

Animals↗
PubMed1996

Generation of antigen-presenting cells for soluble protein antigens ex vivo from peripheral blood CD34+ hematopoietic progenitor cells in cancer patients.

Peripheral blood CD34+ hematopoietic cells (PBPC) mediate hematopoietic reconstitution in cancer patients after autologous transplantation and can be expanded ex vivo in the presence of colony-stimulating factors. This study shows that functionally active antigen-presenting cells (APC) for soluble proteins are generated and expanded in these PBPC cultures. CD34+ cells were cultured ex vivo in medium containing stem cell factor, interleukin-1 beta (IL-1 beta), IL-3, IL-6, and erythropoietin (EPO). The cells from these cultures developed into very potent APC of tetanus toxoid and purified derivative of tuberculin for autologous T cells in vitro. The antigen-presenting capacity of these cell was maintained for at least 38 days of culture. These APC resembled immature cells of the myelomonocytic cell lineage by surface marker, immunocytochemistry and ultrastructural analysis. Such APC might be able to present antigens from certain tumors to the immune system.

Antigen-Presenting Cells↗
PubMed1996

Efficient targeting of the IL-4 gene in a BALB/c embryonic stem cell line.

Embryonic stem (ES) cell lines have been derived from the inner cell mass of day 3.5 blastocysts of the inbred mouse strain BALB/cJ. Twenty-three lines were karyotyped and three were selected for injection into C57BL/6J host blastocysts. Two of the three lines, BALB/c-I and BALB/c-IV, produced germ-line chimaeras. The suitability of the BALB/c-I line for gene targeting experiments was tested by transfecting a targeting construct for the interleukin-4 (IL-4) gene. Transfected BALB/c-I cells exhibited efficient homologous recombination of the targeting vector and transmitted the induced mutation through the germline. This newly-characterized BALB/c-ES cell line thus provides an alternative to the traditional 129-derived and the recently described C57BL/6 embryonic stem cell lines, and will be useful in disrupting genes involved in the immune system. Furthermore, the genetically pure BALB/c IL-4 deficient mice will aid in studying the role of IL-4 in several infectious disease models in which the BALB/c mouse is a susceptible strain.

Animals↗
PubMed1996

IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses.

Mice deficient in interleukin-5 (IL-5-/- mice) were generated by gene targeting in embryonal stem cells. Contrary to previous studies, no obligatory role for IL-5 was demonstrated in the regulation of conventional B (B-2) cells, in normal T cell-dependent antibody responses or in cytotoxic T cell development. However, CD5+ B cells (B-1 cells) in the peritoneal cavity were reduced by 50%-80% in 2-week-old IL-5-/- mice, returning to normal by 6-8 weeks of age. The IL-5-/- mice did not develop blood and tissue eosinophilia when infected with the helminth Mesocestoides corti, but basal levels of eosinophils with normal morphology were produced in the absence of IL-5. IL-5 deficiency did not affect the worm burden of infected mice, indicating that increased eosinophils do not play a significant role in the host defence in this parasite model.

Animals↗
PubMed1996

Role of c-myc and CD45 in spontaneous and anti-receptor-induced apoptosis in adult murine B cells.

Although adult murine B cells can be stimulated to proliferate by Igm receptor cross-linking, we and others have shown that these cells will undergo apoptosis in vitro in a dose-, time- and temperature-dependent manner with polyclonal but not monoclonal anti-IgM, To test the role of c-myc and cell cycle progression in B cell apoptosis, we examined normal, Sp6 anti-TNP lg and E micro-myc transgenic splenocytes for receptor-mediated apoptosis in vitro. In normal mice, both spontaneous and anti-IgM-induced programmed cell death were specifically blocked by antisense oligodeoxynucleotides for the c-myc proto-oncogene, whereas nonsense myc oligonucleotides and irrelevant oligonucleotides had only a minor effect. Similarly, TNP-dextran-induced apoptosis in Sp6 anti-TNF transgenics was inhibited by antisense c-myc. This effect was not due to the mitogenic effects of unmethylated CpG-containing sequences because ones lacking this motif, as well as methylated oligonucleotides containing this motif, prevented apoptosis, and mitogenic doses of lipopolysaccharide failed to inhibit anti-IgM-driven cell death. Importantly, antisense c-myc also prevented the anti-IgM-induced increase in myc protein species. Moreover, spontaneous apoptosis in vitro was exaggerated in E micro-myc transgenic B cells. To examine the role of CD45 in anti-IgM-induced apoptosis, we treated spleen cells from CD45 knockout mice, which do not proliferate with anti-IgM, and found that B cells from these underwent apoptosis normally despite the lack of entry into S. These data suggest that anti-IgM driven apoptosis does not require CD45. Rather, apoptosis may be due to an overexpression of myc protein in the absence of signals which can drive B cells productively into S, but the failure to proliferate normally is insufficient for apoptosis to occur.

Animals↗
PubMed1996

[Are there pathogenicity factors in fungi?].

Since many years so-called pathogenicity or virulence factors of pathogenic bacteria have been studied intensively. Whereas these factors are produced especially by obligate but also facultative pathogenic bacteria, their presence and function in pathogenic fungi is still a matter of debate. In this minireview we summarize some data about possible pathogenicity factors of Cryptococcus neoformans, Aspergillus fumigatus and Candida albicans. The production of adhesins, proteases and capsules contributes to the virulence of these fungi. As fungal infections usually affect immunocompromised patients, the immune status of the host plays a decisive role in addition to the virulence factors produced by fungi.

AIDS-Related Opportunistic Infections↗
PubMed1996

HTLV-I-associated adult T cell leukemia/lymphoma in two patients from Bucharest, Romania.

Two middle-aged patients with T cell lymphoma, both natives of Bucharest, Romania, tested positive for HTLV-I antibodies. Malignant cells had the typical phenotype and morphology of adult T cell leukemia/lymphoma (ATL). Both cases presented with extranodal manifestation, hypercalcemia, early recurrence after initial responses to therapy, and subsequent resistance to conventional and intensified chemotherapy. Infection with HTLV-I was confirmed by PCR analyses of serial biopsies. Neither patient reported known risk factors for HTLV-I infection. This report points to the possibility that Romania may represent an endemic area for HTLV-I and should heighten the awareness towards HTLV-I infections in Romanian patients.

Adult↗
PubMed1996

[Correlation between endometriosis and fallopian tube patency in sterility patients especially after microsurgical sterility operations].

In 130 sterile women undergoing first look laparoscopy we found in 86.9% patent tubes. In this group in 34.5% an endometriosis was discovered. All patients with closed tubes had no signs of endometriosis. In a second look laparoscopy we found in 50% an endometriosis after microsurgery if the tubes were open. In this group we didn't also find an endometriosis if the tubes were closed. The frequency of endometriosis in women with laparoscopic sterilisation is 3.3%. After microsurgery in sterile women a second look laparoscopy seems to be very necessary to check the operation success and to exclude an endometriosis.

Adult↗
PubMed1995

[Collagenous sprue].

HISTORY AND FINDINGS: A 45-year-old man with type I diabetes mellitus was admitted to hospital because of colicky abdominal pain and 5-6 watery stools daily. Upper gastrointestinal endoscopy showed nearly total atrophy of the villi in the duodenum and jejunum suggesting coeliac disease. However, gluten-free diet for 2 weeks brought no improvement. Another examination of the biopsy 6 weeks after the first endoscopy revealed extensive collagen deposition in the lamina propria of the small intestine, giving the diagnosis of collagenous sprue. TREATMENT AND COURSE: Parenteral nutrition, lactulose, cisapride, cholestyramine, doxycycline, paromomycin, vancomycin and octreotide failed to affect the loss of fluid from the gut which 12 weeks after admission had increased to 221 daily. However, it was stopped after prednisolone was administered (100mg daily). 7 months after starting the steroid treatment the collagen layer had disappeared and the villous atrophy had partially regressed. Over the next 6 months the prednisolone dosage was decreased to 10 mg daily. Shortly thereafter a perimembranous glomerulonephritis occurred, with proteinuria (up to 60 g/d) and oedema. It regressed to 6 g/d when the steroid dose was increased and cyclosporin, 0.5 g/d, had been added. On maintenance dosage of cyclosporin the histological and clinical remission of the collagenous sprue has now lasted for over 2 years. CONCLUSIONS: This case suggests that steroid administration is an effective treatment of collagenous sprue. The presence of diabetes and other immune-related diseases in this case also suggests that an immunological mechanism may play a causative role in collagenous sprue.

Anti-Inflammatory Agents↗
PubMed1995

Delineation of the dendritic cell lineage by generating large numbers of Birbeck granule-positive Langerhans cells from human peripheral blood progenitor cells in vitro.

It is well established by in vivo and in vitro studies that dendritic cells (DCs) originate from hematopoietic progenitor cells. However, the presumed intermediate of Birbeck granule (BG)+ Langerhans cells (LCs) has not been detected in cultures derived from bone marrow or peripheral blood progenitor cells (PBPCs), thus contrasting with the data obtained with cord blood. We show here that large numbers of BG+ LCs can be generated from human CD34+ PBPCs in vitro, when granulocyte-macrophage colony-stimulating factor and interleukin-4, potent promotors of LC/DC differentiation, are combined with a cocktail of early acting hematopoietic growth factors. LCs were found to emerge from CD33+CD11b+CD14- progenitor cells that they share with the monocytic lineage. During culture, these cells exhibited a sequence of dramatic morphologic changes, starting with a major increase in granularity followed by an increase in size herein exceeding that of all peripheral blood cells. At the same time, CD1a and major histocompatibility complex class II expression were upregulated and virtually all CD1a++ cells were BG+ by electron microscopy. With prolonged culture, CD1a was downregulated on a major population of cells, paralleled by a loss of BG and an increase of CD4, CD25, and CD80 expression that may correspond to the maturation of epidermal LC in vitro. However, these cells were consistently CD5- and did not exhibit changes in the CD45-isoform expression during culture. The availability of large numbers of these highly purified BG+ LCs and mature DCs allows for specific analysis of these subpopulations and provides a source of potent antigen-presenting cells from individual patients for vaccination protocols against infectious or tumor-associated antigens.

Antigen-Presenting Cells↗
PubMed1995

Interleukin 6 is essential for in vivo development of B lineage neoplasms.

Interleukin (IL) 6 has been suggested to be the major cytokine responsible for proliferation of neoplastic plasma cells in both human myeloma and mouse plasmacytoma. Much of the evidence supporting this suggestion is derived from in vitro studies in which the survival or proliferation of some plasma cell tumors has been found to be IL-6 dependent. However, it remains unclear whether this dependency is the consequence of in vivo or in vitro selective pressures that preferentially expand IL-6-responsive tumor cells, or whether it reflects a critical in vivo role for IL-6 in plasma cell neoplasia. To address this question, we have attempted to induce plasma cell tumors in normal mice and in IL-6-deficient mice generated by introduction of a germline-encoded null mutation in the IL-6 gene. The results demonstrate that mice homozygous (+/+) or heterozygous (+/-) for the wild-type IL-6 allele yield the expected incidences of plasma cell tumors. In contrast, mice homozygous for the IL-6-null allele (-/-) are completely resistant to plasma cell tumor development. These studies define the essential role of IL-6 in the development of B lineage tumors in vivo and provide experimental support for continued efforts to modulate this cytokine in the treatment of appropriate human B cell malignancies.

Alleles↗
PubMed1995

Transitional B cells are the target of negative selection in the B cell compartment.

B lymphocytes recognize antigen through membrane-bound antigen-receptors, membrane IgM and IgD (mIgM and mIgD). Binding to foreign antigens initiates a cascade of biochemical events that lead to activation and differentiation. In contrast, binding to self-antigens leads to death or to inactivation. It is commonly believed that the B cells acquire the ability to discriminate between self and nonself in the early phases of development. We report here that immature B cells, which have just emerged from the mIgMneg, B220pos pool, are not deleted upon binding of self-antigen. In vivo, developing B cells become sensitive to tolerance induction in a relatively late window of differentiation, when they are in transition from the immature (HSAbright, B220dull) to the mature (HSAdull, B220bright) stage. In the transitional B cells, early markers of differentiation such as Pgp1 (CD44) and ThB reach the highest level of expression, while the expression of CD23 and mIgD, late markers of differentiation, and expression of class II MHC, progressively increases. Most of the transitional B cells, but only few of the mature and of the immature B cells, express the fas antigen, while mature B cells, but not immature and transitional B cells, express bcl-2 protein. mIgM is present in low amounts in immature B cells, reaches the highest level of expression in transitional B cells and is down-regulated in mature resting B cells, where it is coexpressed with mIgD. The high expression of mIgM, the presence of the fas antigen and the absence of bcl-2 protein is compatible with the high sensitivity of transitional B cells to negative selection. In vitro, immature B cells die rapidly by apoptosis after cross-linking of mIgM. This result, combined with the resistance of immature B cells to elimination in vivo, suggests that early in development the stroma cell microenvironment modulates signals transduced through mIgM. The functional and phenotypic division of IgMpos bone marrow B cells in three compartments not only allows to define the target population of physiological processes like negative selection, but will also be a helpful tool for an accurate description of possible developmental blocks in mutant mice.

Animals↗